1. Field of the Invention
The present invention relates to novel water-soluble prodrugs of aliphatic or aromatic hindered hydroxyl group containing pharmaceuticals. Particularly, the present invention concerns novel water-soluble phosphonooxymethyl ethers of hindered alcohol and phenol containing pharmaceuticals, such as camptothecin, propofol, etoposide, Vitamin E and Cyclosporin A. The present invention also relates to intermediates used to create the final prodrugs as well as pharmaceutical compositions containing the novel compounds.
2. Background Art
The successful delivery of a pharmaceutical to a patient is of critical importance in the treatment of disorders. However, the use of many clinical drugs with known properties is limited by their very low water solubility. As a result of low water solubility these drugs must be formulated in co-solvent pharmaceutical vehicles, including surfactants. These surfactants have been shown to lead to severe side effects in humans that limit the clinical safety of these drugs and therefore the treatment of several disorders.
For example, camptothecin is a natural product isolated from barks of the Chinese camptotheca tree, Camptotheca accuminata. It has been shown to have strong anti-tumor activity in several in vivo animal models including major tumor types such as lung, breast, ovary, pancreas, colon and stomach cancer and malignant melanoma. Camptothecin inhibits the cellular enzyme DNA topoisomerase I and triggers a cascade of events leading to apoptosis and programmed cell death. Topoisomerase I is essential nuclear enzyme responsible for the organization and modulation of the topological feature of DNA so that a cell may replicate, transcribe and repair genetic information. 
The serious drawback of camptothecin is its very limited water solubility. For biological studies it is necessary to dissolve the compound in a strong organic solvent (DMSO) or to formulate the drug as a suspension in Tween 80:saline which is an undesirable drug formulation for human therapy. Recently two analogs of camptothecin with moderate water solubility have been approved in United States for treatment of advanced ovarian cancer (Hycamtin) and colorectal cancer (Camptosar).
Other drugs, like camptothecin, that have similar problems are cyclosporin A (CsA), propofol, etoposide and Vitamin E (alpha-tocopherol). Like camptothecin, CsA has within its structure a sterically hindered alcohol, a secondary alcohol in this case. CsA is formulated in a CremophorEL/ethanol mixture. 
An example of a sterically hindered, poorly water soluble phenol is propofol, an anesthetic. 
Propofol is formulated for i.v. clinical use as a o/w emulsion. Not only is propofol poorly water soluble, but it also causes pain at the site of injection. This pain must be ameliorated by using lidocaine. Due to the fact that it is formulated as an emulsion, it is difficult and questionable to add other drugs to the formulation and physical changes to the formulation such as an increase in oil droplet size can lead to lung embolisms, etc. A water soluble and chemically stable prodrug of propofol would provide several advantages. Such a formulation could be a simple aqueous solution that could be admixed with other drugs. If the prodrug itself was painless, the prodrug may be more patient friendly, and finally there should be no toxicity due to the vehicle. Other poorly water soluble, sterically hindered phenols are the anticancer drug, etoposide and Vitamin E (alpha-tocopherol).
The present invention provides a water soluble form of alcohol and phenol containing drugs such as camptothecin and propofol. With respect to camptothecin, compounds according to the present inventions are phosphonooxymethyl ethers of camptothecin in the form of the free acid and pharmaceutically acceptable salts thereof. The water solubility of the acid and the salts facilitates preparation of pharmaceutical formulations. All of the prodrugs according to the present invention exhibit superior water solubility compared to their respective parent drugs. The methods developed for the compounds of the present invention can be useful for conversion of many other water insoluble medicinal agents having aliphatic or aromatic hindered hydroxyl groups to the water soluble derivatives.
The invention described herein involves new compositions of matter. The invention relates to the water soluble phosphonooxymethyl derivatives of alcohol and phenol containing pharmaceuticals represented by the general formula I: 
The above formula I is the derivative of ROH, wherein ROH represents an alcohol- or phenol-containing drug, such as camptothecin, propofol, etoposide, vitamin E and cyclosporin A. In the above formula I, n represents an integer of 1 or 2. When n is 2, ROH is preferably a phenol-containing pharmaceutical, such as propofol. Also included are some drugs for which injectable forms are not possible due to their inherent poor water solubility. These include danazol, methyltestosterone, iodoquinol and atovaquone. R1 is hydrogen or an alkali metal ion including sodium, potassium or lithium or a protonated amine or protonated amino acid or any other pharmaceutically acceptable cation. R2 is hydrogen or an alkali metal ion including sodium, potassium or lithium or a protonated amine or a protonated amino acid or any other pharmaceutically acceptable cation. After intravenous or oral administration, the derivatives according to formula I are converted back to the parent drugs by hydrolysis and/or phosphatase.
Accordingly, it is an object of the present invention to develop derivatives of water insoluble drugs which exhibit good activity and water solubility.
It is another object of the present invention to develop pharmaceutical compositions of these water soluble compounds, which comprises an amount of the compound of formula I and a pharmaceutically acceptable carrier.
It is another object of the present invention to develop drug derivatives having good stability at pH levels suitable for making pharmaceutical formulations, but quickly break down in vivo under physiological conditions, to potentially act as prodrugs.